Adult-based genetic risk scores for insulin resistance associate with cardiometabolic traits in children and adolescents

Context: Insulin resistance (IR) is a key factor in the development of cardiometabolic diseases. While genetic risk scores (GRSs) for IR have been developed and validated in adult population, it is unclear if they can be used for risk assessment in youth.

Objective: Our objective was to investigate whether adult-derived genetic risk scores (GRSs) for insulin resistance (IR) associate with cardiometabolic traits in children and adolescents.

Methods: We studied a group of children and adolescents with obesity (n= 1,680) and a group without obesity (n=1,804). We constructed three GRSs based on fasting (IR-GRS27), oral glucose tolerance test (IR-GRS8), and IR-related phenotypes (IR-GRS51) from previous genome-wide association studies. Using an additive genetic model, we calculated weighted GRSs and analysed their associations with cardiometabolic traits using linear and logistic regression models.

Results: The IR-GRS27 was associated with higher serum concentrations of fasting insulin, C-peptide, triglyceride (TG), gamma-glutamyl transferase and alanine aminotransferase (ALT), and homeostatic model assessment of insulin resistance. The IR-GRS27 was furthermore associated with higher prevalence of IR and ALT. IR-GRS51 was associated with higher TG and lower high-density lipoprotein cholesterol, while IR-GRS8 associated with lower total cholesterol, low-density lipoprotein cholesterol, and increased ALT. IR-GRS27 and IR-GRS8 were additionally associated with higher prevalence of IR and steatotic liver disease respectively.

Conclusion: Adult-derived GRSs for IR are significantly associated with cardiometabolic traits in children and adolescents. If validated in independent study samples, our findings suggest the contribution of adult-based GRSs in assessing IR-related cardiometabolic risk in youth.